The beneficial effects of exercise training in humans on cardiovascular risk factors and other systemic markers of health are well documented, but the molecular pathways mediating these improvements are poorly understood. Many changes are known to be mediated primarily through adaptations in skeletal muscle. Yet, attempts to study mechanistic relationships in humans between exercise-induced responses in skeletal muscle and systemic measures of health have been plagued by the lack of carefully defined exercise programs and the lack of coupled techniques able to address molecular responses in samples of human tissues. The STRRIDE study addressed each of these problems, wherein a randomized, controlled exercise program with varying exercise dose/intensity was used for an at-risk population of subjects. This study featured clinical marker measures of cardiovascular health and concomitant muscle tissue sampling (at baseline, post-training and during detraining). Preliminary analysis of gene expression in muscle biopsy samples within the highest dose group has revealed several promising pathways for study. First, training effects on several key metabolic enzymes were found, some of which were gender-specific. Second, strong induction of muscle and systemic fibrinolytic genes was found. Due to the small sample sizes used in these preliminary studies and the lack of testing to date for effects of exercise intensity and duration, the current study seeks to expand these findings and fully detail molecular remodeling within skeletal muscle given exercise training in at risk subjects, and to correlate these changes to improvements in systemic measures of health.